In the field of radioimmunotherapy, the radioisotope chosen is determined, at least in part, by the type of disease to be treated. The reason for this is that the type of particles emitted by a given radioisotope are directly related to tissue penetration and the ability of the isotope to kill cells (Boll et al., Radiochim. Acta 79: 87–91 (1997)). β-emitters, like 90Y and 131I, which have a tissue range of several millimeters, have been used successfully to treat solid tumors (Boll et al. (1997), supra). However, a tissue range of several millimeters is not optimal for the treatment of single cells, small clusters of cells, micrometastatic disease, leukemias and lymphomas (Jurcic et al., In: Cancer Chemotherapy and Biological Response Modifiers Annual 17, Pinedo et al., eds., New York: Elsevier B. V. (1998), pp. 195–216; Falini et al., Cancer Surveys 30: 295–309 (1998)). α-emitters, on the other hand, combine high cytotoxicity with a short tissue range, i.e., less than about 150μ (Boll et al. (1997), supra). Alpha radiation can kill a cell with only one hit to the nucleus and will kill substantially any cell with 10 hits or less. Consequently, considerable effort has been expended in the development of the α-emitters 212Bi (t1/2=60 min) (Ruegg et al., Cancer Res. 50: 4221–4226 (1990)), 213Bi (tl/2=45 min) (Geerlings et al., Nucl. Med. Comm. 14: 121–125 (1993)), and 211At (t1/2−7.2 hr) (Lambrecht et al., Radiochim. Acta 36: 443–440 (1985)). However, 212Bi, 213Bi and 211At suffer from disadvantages. The short half-life of 212Bi and 213Bi limit their application. The limited available of 211At, due to half-life and production constraints, limits its utility. Consequently, 225Ac, which is highly cytotoxic, has been proposed as an alternative α-emitter to 212Bi, 213Bi and 211At for use in radioimmunotherapy.
225Ac decays through a chain of four α emissions and two β emissions to the stable isotope 209Bi, thereby releasing a large amount of energy (28 MeV) (Davis et al., Nucl. Med. Biol., accepted; Alleluia et al., In: Gmelin Handbook of Inorganic Chemistry, 8th ed., Kugler et al., eds., New York: Springer-Verlag (1981), pp. 181–193). Unfortunately, most of the 225Ac administered in a dose is deposited in the liver and bone (Beyer et al., Isotopenpraxis 26: 111–114 (1990)). Thus, numerous attempts have been made to reduce the toxicity of 225Ac through chelation with, for example, citrate (Beyer et al. (1990), supra), EDTMP (ethylenediaminetetramethylenephosphonic acid; Beyer et al., Nucl. Med. Bio. 24:367–372 (1997)), EDTA (ethylenediaminetetraacetic acid; Alleluia et al. (1981), supra) and CHXA″-DTPA (N-[(R)-2-amino-3-(4-nitrophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N′,N′,N′-pentaacetic acid; Davis et al., supra). While these chelates reduce the liver dose somewhat, CHXA″-DTPA, which is the best 225Ac chelate to date, still has a maximum tolerated dose (MTD) of approximately 100 kBq in mice and higher doses of 225Ac-CHX-DTPA have resulted in 100% mouse mortality within eight days (Davis et al., supra).
Thus, while 225Ac is potentially useful in radioimmunotherapy, a suitable chelate is needed. Until now, a suitable chelate with sufficient in vivo stability had yet to be discovered. Accordingly, it is an object of the present invention to provide such a chelate and related compounds. It is another object of the present invention to provide methods of synthesizing such a chelate and related compounds. It is yet another object of the present invention to provide methods of using such a chelate and related compounds. These and other objects, as well as additional advantages and inventive features, will become apparent from the detailed description provided herein.